City of Hope Physicians Announce CAR T Cell Breakthroughs at ASH

January 6, 2018 | by Letisia Marquez

Budde-Elizabeth Elizabeth Lihua Budde, M.D., Ph.D.
New blood cancer breakthroughs – including several involving CAR T cell therapy – were announced by City of Hope physicians at the American Society of Hematology (ASH) annual meeting in Atlanta.

Among the announcements, City of Hope doctors revealed that patients whose acute myeloid leukemia (AML) was no longer responding to standard therapies, along with a patient with a rare blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN), achieved a complete response after undergoing treatment with CAR T cell therapy. The results from the phase 1 clinical trial were reported at ASH.

Of note, the City of Hope BPDCN patient is the first to achieve a complete response to a CAR T cell therapy; this is also the first in-human trial for AML and BPDCN patients using a CD123 CAR T cell therapy.

The therapy, which was developed at City of Hope and is a Mustang Bio Inc. (a Fortress Biotech Company) product, was also safe and well-tolerated in patients enrolled in the phase 1 clinical trial.

“This is a very promising CAR T cell therapy for AML and BPDCN patients and furthermore, the side effects they experienced from the therapy were treatable and manageable,” said Elizabeth Lihua Budde, M.D., Ph.D., an assistant professor in City of Hope Department of Hematology & Hematopoietic Cell Transplantation, who reported on the study at ASH. “We are hopeful that the MB-102 CAR T therapy will lead to a more effective treatment option for these patients, who currently have few therapies available to them.”

All six patients in the AML cohort had refractory AML following allogeneic hematopoietic stem cell transplant, and a median of six prior lines of therapy. Two patients were treated at the first dose level, and one patient achieved a morphologic leukemic-free state, which lasted two months. She received a second infusion three months later with subsequent blast reduction from 77.9 percent to 0.9 percent (flow cytometry) after 35 days.

Of the four patients on the second dose level, one patient achieved a complete response with incomplete count recovery and proceeded to a second allogeneic hematopoietic stem cell transplant on day 70. After 161 days post-transplant, she was cancer-free with good engraftment and 100 percent donor chimerism. Another patient with morphologic remission prior to treatment remained in complete remission at day 28 and proceeded to a second stem cell transplant. The remaining two patients had reductions in blast counts, but did not achieve a complete response.

All health complications, including cytokine release syndrome, pneumonia and a rash due to drug hypersensitivity, were reversible and manageable. There were no dose limiting toxicities and no treatment-related cytopenias (or a reduction in the number of mature blood cells.)

One BPDCN patient — a 74-year-old man with a persistent bulky subcutaneous mass — has been treated so far. Following lymphodepletion, he received a single dose of autologous CD123 CAR T cells and was in complete response at 60 days post-infusion. The patient tolerated the treatment well with no cytokine release syndrome or neurologic toxicity.

“Infusions of up to 200M CAR T cells are safe with no GVHD [graft-versus-host disease], neurologic toxicity or dose limiting toxicities,” Budde said. “Correlative studies are ongoing to identify potential biomarkers of response and resistance, evaluate the impact on hematopoiesis, and of CD123 expression levels on AML blast cells.”

JCAR017, CAR T cell therapy for aggressive B cell non-Hodgkin lymphoma
 
Tanya Siddiqi, M.D., assistant clinical professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, reported on patients’ characteristic and biomarkers in the first multicenter phase 1 trial of JCAR017, a Juno Therapeutics CAR T cell therapy that targets CD19 cells in refractory/relapsed aggressive B cell non-Hodgkin lymphoma at the ASH annual meeting.
 
Tanya Siddiqi Tanya Siddiqi, M.D.
JCAR017 (lisocabtagene maraleucel/liso-cel) is a defined composition CAR T cell product administered at precise doses of CD4+ and CD8+ CAR T cells. The trial hypothesized that the lack of product variability may better enable the identification of baseline patient factors that are associated with clinical outcomes.
 
To that end, Siddiqi and fellow researchers performed exploratory analyses that show that baseline (immediately pre-lymphodepletion) patient characteristics like a high tumor burden (a high number of cancer cells or tumors), high LDH (a metabolic enzyme in cancer cells) and elevated levels of inflammatory markers, such as ferritin, are associated with higher CAR T cell expansion and increased rates of cytokine release syndrome and neurotoxicity. (The overall toxicities of CRS and NT were relatively low, 30 and 20 percent respectively.)
 
“However, it may be possible to plan trials in the future around strategies to reduce risk of toxicity in patients with higher baseline burden of disease, higher LDH and inflammatory state.” Siddiqi said. “Such patients also have higher expansion of CAR T cells in their blood but durability of responses seem to be lower in them at the three-month mark post-CAR T cells, possibly due to rapid T cell exhaustion.”

Preliminary modeling efforts suggest that a therapeutic window may exist for CAR T cell expansion that could limit toxicity and optimize efficacy, Siddiqi added.
 
“We may be able to drive all patients into this window by identifying patients at risk for low or high CAR T cell expansion and evaluating strategies to enhance or limit CAR T cell expansion,” Siddiqi added. “Our goal is to attain the Holy Grail of durable complete responses in all patients with aggressive lymphomas.”
 
Phase 1/2 Clinical Trial Outcomes for Combination Immunotherapy Show Promise in Relapsed and Refractory Hodgkin Lymphoma Patients
 
Alex Herrera, M.D., assistant professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, presented positive results from a clinical trial using a combination of two immunotherapy drugs — brentuximab vedotin and nivolumab — at the ASH annual meeting.
 
Alex Herrera Alex Herrera, M.D.
The study, led by Herrera and involving cancer researchers from around the county, tested the combination therapy in patients with classical Hodgkin lymphoma whose cancer had relapsed or was resistant to traditional therapies. This population accounts for 10 to 30 percent of Hodgkin lymphoma patients, who are typically treated with traditional and often harsh chemotherapies followed by an autologous stem cell transplant, which uses a patient’s own stem cells.
 
Sixty-two patients were enrolled to test whether brentuximab vedotin and nivolumab might be a more tolerable way for patients to fight the disease before a transplant. Participants received brentuximab vedotin and nivolumab as an outpatient regimen in three-week cycles for up to 12 weeks. The complete response rate among all treated patients was 61 percent, while the overall response rate, which includes those participants who had a partial response, was 82 percent. For those patients who did not have a complete response, most were able to respond to subsequent therapies and proceed with a stem cell transplant.
 
“The combination was a safe, well-tolerated and highly effective bridge to transplantation,” Herrera said. The study results were also published in the latest version of the journal Blood.
 
Brentuximab vedotin is an antibody-based treatment that targets delivery of chemotherapy only to Hodgkin lymphoma cells; nivolumab works by blocking the PD-1 immune checkpoint pathway, which tumors often hijack to evade the immune system. Funding for the clinical trial was provided by Seattle Genetics Inc. through the joint financial support of Seattle Genetics Inc. and Bristol-Myers Squibb.
 
“Now we have shown that the combination is an effective second-line treatment for Hodgkin lymphoma and future trials could explore the role of this regimen in comparison to traditional second-line chemotherapy,” Herrera said.  
 
The treatment regimen is also being studied in many settings, including as an initial treatment for elderly patients who are not eligible for chemotherapy and for patients who have relapsed after an autologous stem cell transplantation.
 
Herrera developed and is leading a clinical trial at City of Hope that will open at five other centers to also test brentuximab vedotin plus nivolumab as consolidation treatment after autologous stem cell transplantation to minimize the likelihood of Hodgkin lymphoma recurrence following the transplant.
 
Treating myelofibrosis patients with the FluMel regimen in stem cell transplantation process
 
Ali-Haris Haris Ali, M.D.
The only treatment that can currently cure myelofibrosis — a rare bone marrow cancer — is a stem cell or bone marrow transplant from a donor, making it crucial that the best therapies are used in the transplant process.
 
City of Hope was one of the first centers nationwide to perform stem cell or bone marrow transplants on myelofibrosis patients, who on average are 65 years old at the time of diagnosis and may have a difficult time coping with traditional high-dose chemotherapy that takes place before a transplant.
 
City of Hope uses a lower intensity chemotherapy known as fludarabine/melphalan (FluMel) to help remove cancerous cells from a patient’s system, a manner of clearing the way for healthy stem cells or bone marrow to be engrafted during a transplant.
 
In the largest study ever examining the effects of the FluMel regimen in 120 allogeneic transplant patients with myelofibrosis, Assistant Clinical Professor Haris Ali, M.D., and Associate Chair David S. Snyder, M.D., both in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, examined how well such patients did and what factors led to the most successful outcomes. All were patients at City of Hope.
 
The overall survival rate after five years was nearly 65 percent for all patients.
 
Snyder-David David S. Snyder, M.D.
Patients with the best overall survival rates were those who received a stem cell donation from a related donor, or 80 percent. But even patients who had an unrelated donor fared well with a 65 percent survival rate after five years.
 
“Transplantation for myelofibrosis patients has a reputation for being too toxic, too risky, and not something doctors or patients should consider,” Snyder said. “Our study demonstrates that given the appropriate therapies in the transplantation process, it is possible for myelofibrosis patients — even those with advanced age or disease — to undergo the procedure and do well.”
 
“Our study demonstrates a promising step in City of Hope’s efforts to provide an alternative to the standard of care for patients with this debilitating disease,” Ali said. “City of Hope is constantly in pursuit of therapies that are less toxic and more effective for our patients.”
 
Another aspect of the study also examined a patient’s prior use of ruxolitinib, a therapy that treats myelofibrosis, and graft-versus-host disease (GVHD), which occurs when the donor’s immune system cells cause inflammation in the patient; the donor’s cells react to the patient as they would a foreign invader and attack the body’s cells.
 
Patients who had taken ruxolitinib previously had an increased risk of developing acute GVHD, possibly due to a condition known as inflammatory cytokine rebound. 
 
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